Malignant peripheral nerve sheath tumors (MPNSTs) are among the most devastating and intractable of the soft tissue sarcomas. MPNSTs are also the most common neurofibromatosis type 1 (NF1)-associated cancer and a leading cause of death in NF1 patients. Taking advantage of the expertise our team has built over the past five years testing single agent treatments in mouse models of MPNST, we propose a set of combination pre-clinical tests to support a next generation of clinical trials. The NF1 gene product, neurofibromin, is an off signal for Ras proteins, resulting in aberrant Ras-Raf-MEK signaling in MPNST cells. Our recent publication shows that a MEK inhibitor effectively delays MPNST growth. In addition we found that an Aurora kinase A (AURKA) inhibitor stops tumor growth. Preliminary data show that a small molecule in combination with an oncolytic virus actually shrinks tumors and induces some cures. This proposal leverages the complimentary expertise of two PIs. In Aim 1Dr. Cripe will lead the studies exploring small molecules combined with oncolytic viral therapy. In Aim 2 Dr. Ratner will combine small molecules to either target G1/S with G2/M inhibition (horizontal inhibition) or enhance G2/M inhibition (vertical inhibition). Together the studies are anticipated to discover therapeutic combinations that cure MPNST in model systems, and can rapidly be moved into clinical trials.